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Research Highlight | May 09, 2023

Study mimicking brain development identifies protein linked to neurodevelopmental disorders

A protein called RuvB-like 2 (RUVBL2) has been linked to certain rare neurodevelopmental disorders following work conducted by a TFRI-funded team based at the Princess Margaret Cancer Centre. The team led by Dr. Phedias Diamandis generated profiles of the proteins found at various stages of development in human brain tissue and in mini brains-in-a-dish. (Dr. Diamandis is a Terry Fox New Investigator studying the role of cancer stem cells in recurrent glioblastoma.)

The brain is the body's most complex organ. It is also one of the most difficult to study because access to human brain tissue is limited. To overcome this limitation, the researchers used small three-dimensional brain-like organs in the lab called cerebral organoids.

"These experimental models have enabled researchers to mimic the development of the brain and to study the biology underlying diseases, such as Alzheimer's disease, Zika virus infection and cancer," says Dr. Diamandis, a neuropathologist at UHN and assistant professor of medicine & pathobiology at University of Toronto.

In the current study, the researchers profiled the proteins expressed in two cell populations within cerebral organoids that represent different stages of brain development. They also profiled proteins in nine regions of the developing human brain.

They found that the profiles of proteins in cerebral organoids were very similar to those found in fetal brain tissue.

"Cell-type specific markers have been key for defining the proteins and pathways involved in the early steps of brain development. But questions remain," says study first author Sofia Melliou, a PhD student in Dr. Diamandis' lab. "By using organoids to characterize changes in proteins in different cell populations – those at early and late stages of development – we were able to open a window into how the brain changes as it grows."

Using this approach, the team identified an intriguing difference between the two populations of cells in cerebral organoids: the cells representing an earlier stage of development exhibited a higher expression of the RUVBL2 protein.

Chemically inactivating RUVBL2 resulted in cell displacement and cell death within the organoids. To see whether what they observed in the lab had any clinical implications, the researchers examined clinical datasets and found that some individuals with neurodevelopmental impairments displayed mutations in the RUVBL2 gene.

Examples of these impairments include mild microcephaly, severe developmental disorder and an abnormal nervous system.

"Our findings illustrate how cell-type specific profiling of these model systems can be a powerful discovery tool for uncovering the underlying mechanisms of brain development and neurological diseases," says Dr. Diamandis.

The work was supported by other funders as well. 

Adapted from a UHN press release.